DAF-16/FOXO and HLH-30/TFEB comprise a cooperative regulatory axis controlling tubular lysosome induction in C. elegans

Cristian Ricaurte-Perez, Joshua P. Gill, P. Kerr Wall, Olga Dubuisson, Kathryn R. DeLeo, K. Adam Bohnert and Alyssa E. Johnson ()
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Cristian Ricaurte-Perez: Department of Biological Sciences
Joshua P. Gill: Department of Biological Sciences
P. Kerr Wall: Department of Biological Sciences
Olga Dubuisson: Department of Biological Sciences
Kathryn R. DeLeo: Department of Biological Sciences
K. Adam Bohnert: Department of Biological Sciences
Alyssa E. Johnson: Department of Biological Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Transcription factors DAF-16/FOXO and HLH-30/TFEB have been linked to aging regulation, but how they synergize to promote longevity is not fully understood. Here, we reveal a functional interaction between these two transcription factors that supports healthier aging in Caenorhabditis elegans. Namely, DAF-16 and HLH-30 cooperate to trigger robust lysosomal tubulation under various contexts, which contributes to systemic health benefits in late age. Remarkably, lysosome tubulation can be artificially induced via overexpression of a small lysosomal gene, dSVIP, in the absence of one transcription factor, but not both. Mechanistically, intestinal overexpression of dSVIP leads to nuclear accumulation of DAF-16 and HLH-30 in gut and non-gut tissues and triggers global gene expression changes, including induction of vps-34 and related lipid-metabolism genes, that promote tubular-lysosome activity. Collectively, our work reveals a cellular process under control of DAF-16 and HLH-30 that elicits pro-health effects in aging.

Date: 2025
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DOI: 10.1038/s41467-025-64832-x

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